INTRODUCTION — Diarrhea can cause significant morbidity in patients with HIV and can be due to a multitude of etiologies from infectious pathogens to malignancy to medications. Diarrhea is also an independent predictor of reduced quality of life and, in the case of advanced HIV disease, increased mortality .
The approach to the evaluation of diarrhea will be discussed here. For detailed information about specific pathogens, please see appropriate topic reviews. (See "AIDS-related cytomegalovirus gastrointestinal disease" and "Mycobacterium avium complex (MAC) infections in persons with HIV".)
●United States – Prior to the use of effective combination antiretroviral therapy (ART) in the United States, chronic diarrhea (defined as four or more weeks of diarrhea) was responsible for 17 percent of the new AIDS diagnoses reported to the Centers for Disease Control and Prevention (CDC) . (See "The natural history and clinical features of HIV infection in adults and adolescents", section on 'AIDS and advanced HIV infection'.)
However, with the widespread use of ART, the incidence of infectious causes of diarrhea in patients with HIV and low CD4 counts (<200 cells/microL) has declined . Experience at a single center between 1995 and 1997 found that, while the incidence of diarrhea remained constant, infectious etiologies declined from 53 to 13 percent . In another study that followed a cohort of approximately 600 patients in the Boston area after the introduction of combination ART, chronic diarrhea was reported in 28 percent and severe diarrhea (defined as more than six stools per day) in 3 percent . In this study, stool pathogens were found in only 12 percent of the population.
Although the incidence of infectious diarrhea has decreased, antiretroviral-associated diarrhea may occur, the frequency depends upon the specific ART regimen (see 'Exposures' below). Medication-induced diarrhea is a leading diagnostic consideration when diarrhea is the sole complaint , particularly when there is a temporal association. In addition, when an infectious etiology is not ascertained in advanced disease, then HIV-associated enteropathy needs to be considered.
●Resource-limited settings – In resource-limited settings, where ART may be less available for a variety of reasons, diarrheal disease remains highly endemic, even for those without HIV . Chronic diarrheal disease in adults in Africa has been used as a predictor of HIV-seropositivity . In addition, children with HIV are more likely to die with diarrhea than children with diarrhea who are not infected with HIV . (See "Use and impact of antiretroviral therapy for HIV infection in resource-limited settings".)
PATHOGENESIS — Diarrheal disease in individuals with HIV is frequently caused by infectious agents but may also be due to infiltrative diseases, such as lymphoma or Kaposi's sarcoma (KS) [10-12].
The infectious pathogens associated with diarrheal disease in HIV infection may vary with the degree of immunocompromise in the host  (table 1). Routine enteric pathogens with sufficient virulence to cause disease in healthy hosts will cause diarrheal disease in individuals with HIV and intact or compromised immunologic function. Less virulent pathogens, which appear to require some immune compromise to establish disease, are more common in patients with more advanced HIV or AIDS. As an example, the enteroaggregative Escherichia coli (EAEC) that are associated with persistent diarrheal disease in children in the developing world but have limited potential to cause diarrhea in volunteers, have been associated with persistent diarrhea in adults with HIV in the United States and Switzerland [13-15]. (See "Pathogenic Escherichia coli associated with diarrhea".)
Pathogens such as Cryptosporidium parvum, which can cause severe diarrheal disease in both immunocompetent and immunocompromised individuals, will become persistent in AIDS patients with CD4 counts <180 cells/microL . By contrast, patients with HIV and a more preserved CD4 count usually have a self-limited illness with this organism. (See "Cryptosporidiosis: Epidemiology, clinical manifestations, and diagnosis".)
The microsporidial organisms, Enterocytozoon bieneusi and Encephalitozoon intestinalis, are rare causes of diarrhea in immunocompetent hosts but have been associated with severe malabsorption and persistent diarrhea in patients with HIV [5,7,17]. Rarely, intestinal spirochetosis due to Brachyspira pilosicoli has been described in patients with HIV and abdominal pain, rectal discharge and bleeding . (See "Microsporidiosis".)
While organisms like Mycobacterium avium complex (MAC) are associated with lung infections in immunocompetent patients with chronic lung disease, they will also produce disseminated disease with bowel infiltration and malabsorption in patients with severe immune compromise . (See "Overview of nontuberculous mycobacterial infections" and "Mycobacterium avium complex (MAC) infections in persons with HIV".)
HIV infection of the gastrointestinal tract is also well documented. HIV infection may play a role in the pathogenesis of diarrhea and gastrointestinal illness, although it is not clear if the mechanism is direct infection of the enterocyte or infection of the lymphoid tissue of the gastrointestinal tract with dysregulation of local cytokine production .
HISTORY — The duration of symptoms, frequency and characteristics of stool, amount and pace of weight loss, and other abdominal or constitutional symptoms should be sought and will assist in placing a patient in the category of having small or large bowel diarrhea.
Medication history and recent changes in medications, status of HIV disease, route of acquisition of HIV disease and other opportunistic illnesses or co-morbid illnesses should be ascertained. Since HIV is currently better suppressed by antiretroviral agents, more patients with HIV are presenting with non-HIV related co-morbid conditions. Thus, it is important to ask about a family history of inflammatory bowel disease that might lead to alternative diagnoses for diarrheal symptoms.
Regional involvement — A careful history can assist in pinpointing the portion of the gastrointestinal tract most severely involved since certain infections have a propensity to involve particular regions.
Small bowel involvement — The small bowel is an organ that has secretory and nutrient-absorbing functions. Disease that is predominantly located in the small bowel is likely to have a presentation that reflects the dysregulation of these two functions. Small bowel diarrhea is usually watery and of large volume; it may be associated with small bowel symptoms such as bloating, gas, cramping, and potentially profound weight loss. Some patients with involvement of the terminal ileum may present with malabsorption of vitamin B12 . Patients with documented evidence of small bowel dysfunction are more likely to have a small bowel pathogen isolated from their stool .
Large bowel involvement — The large bowel is a storage organ where some additional absorption of water occurs. Large bowel diarrhea is characterized by frequent, small volume, often painful stools. Malabsorption of nutrients does not occur in diarrhea that is limited to the large bowel. Thus, nutritional compromise does not occur in patients who have infection confined to the large bowel, unless the pathogen is also capable of causing a disseminated infection with a "typhoidal" presentation. In patients with HIV, the typhoidal syndrome may be caused by Salmonella or by disseminated infection due to a range of organisms including cytomegalovirus (CMV), MAC, M. tuberculosis, or fungi, such as Histoplasma or Cryptococcus. (See "AIDS-related cytomegalovirus gastrointestinal disease" and "Mycobacterium avium complex (MAC) infections in persons with HIV".)
Anorectal involvement — Patients with a history of unprotected receptive anal intercourse prior to the development of severe tenesmus, dyschezia and urgency, localizes the process to the anorectum.
Symptoms — It is also important to ascertain the nature and chronicity of symptoms as well as the most recent CD4 cell count, which will directly impact on diagnostic considerations. As noted above, patients with CD4 cell counts <100 cells/microL are at risk for opportunistic infections which are typically chronic, such as Cryptosporidium, MAC, CMV, Isospora, or Microsporidium.
●Upper or mid-abdominal cramps, bloating, and nausea suggest gastric or small bowel involvement, or both, which would be more common in MAC, Cryptosporidium, Giardia, or Isospora belli infections. (See "Cryptosporidiosis: Epidemiology, clinical manifestations, and diagnosis" and "Epidemiology, clinical manifestations, and diagnosis of Cystoisospora (Isospora) infections" and "Giardiasis: Epidemiology, clinical manifestations, and diagnosis" and "Mycobacterium avium complex (MAC) infections in persons with HIV".)
●Severe watery diarrhea resulting in dehydration, electrolyte disturbances, and weight loss suggests intestinal cryptosporidiosis, or infection with certain E. coli. (See "Cryptosporidiosis: Epidemiology, clinical manifestations, and diagnosis" and "Pathogenic Escherichia coli associated with diarrhea".)
●Hematochezia, tenesmus, and lower abdominal cramps usually imply colonic infection caused by opportunistic pathogens such as CMV, or less commonly HSV, or bacterial infections, such as Salmonella, Yersinia, Shigella, or Campylobacter. If the patient is severely immunocompromised, these bacterial infections can follow a severe, chronic, or relapsing clinical course in association with extraintestinal symptoms . Lower gastrointestinal bleeding has been uncommonly associated with Kaposi's sarcoma and Bartonella infection . (See "AIDS-related Kaposi sarcoma: Staging and treatment" and "Bartonella infections in people with HIV".)
●Weight loss accompanying chronic diarrhea may suggest an opportunistic infection, infiltrative disease, or presence of malabsorption or small bowel overgrowth syndrome.
Exposures — An epidemiologic history concentrating on exposures should be ascertained:
●The patient should be interviewed about travel history , sexual exposures, pet exposures, water sources, food associations (lactose intolerance), or other significant past medical history (eg, chronic pancreatitis) [25,26]. (See "Travelers' diarrhea: Epidemiology, microbiology, clinical manifestations, and diagnosis".)
●A history of unprotected receptive anal intercourse may suggest sexual transmission of organisms such as Herpes simplex virus (HSV), Neisseria gonorrhea, Chlamydia, Shigella, or occasionally Entamoebae . (See "Evaluation of anorectal symptoms in men who have sex with men" and "Epidemiology, clinical manifestations, and diagnosis of genital herpes simplex virus infection" and "Clinical manifestations and diagnosis of Neisseria gonorrhoeae infection in adults and adolescents", section on 'Proctitis' and "Intestinal Entamoeba histolytica amebiasis", section on 'Clinical manifestations' and "Clinical manifestations and diagnosis of Chlamydia trachomatis infections", section on 'Proctitis and rectal infection'.)
●In patients who are taking antiretroviral therapy, medication-induced diarrhea should be considered, particularly when diarrhea is the sole presenting symptom .
•Diarrhea is most common with pharmacologically boosted protease inhibitors. Diarrhea has also been associated with the use of integrase strand transfer inhibitors, but it is less likely to occur. When diarrhea is seen in the setting of an INSTI, it is most likely to occur with boosted elvitegravir. (See "Overview of antiretroviral agents used to treat HIV".)
•When diarrhea is associated with the use of nucleos(t)ide agents (NRTIs), it may be related to mitochondrial toxicity, especially if the patient presents with bloating, nausea, and mild abdominal pain . However, mitochondrial toxicity with the commonly used NRTIs is rare. (See "Mitochondrial toxicity of HIV nucleoside reverse transcriptase inhibitors".)
●Clostridioides difficile is an important diagnostic consideration in the patient with HIV who has had recent exposure to antibiotics. In a retrospective study of more than 11,000 episodes of diarrheal illness among patients with HIV, C. difficile was the most commonly identified pathogen, accounting for 54 percent of all bacterial agents .
●The intestinal microbiome is altered in individuals infected with HIV [31,32], and may be further altered by the use of antibiotics. However, the clinical significance of these changes in the microbiome is unclear and further study is required.
PHYSICAL EXAMINATION — A careful physical examination is necessary to help determine the degree of wasting or any particular findings that may point to specific diseases.
●Height, weight, and calculation of body mass index (BMI) will assist in determining nutritional status.
●A drop in blood pressure or increase in pulse with standing suggests significant volume depletion.
●Tenting of skin and dry mucous membranes may reflect volume status or deficiencies of micronutrients, which could accompany a small bowel process. (See 'Small bowel involvement' above.)
●Fever in an immunosuppressed host may indicate uncontrolled HIV replication, or the possibility of opportunistic infections such as cytomegalovirus (CMV), Mycobacterium avium complex (MAC), and other pathogens.
●Fever and weight loss accompanied by hepatosplenomegaly may suggest a systemic infiltrative process, such as MAC, histoplasmosis, or lymphoma.
●Abdominal tenderness may indicate the possibility of an abdominal abscess, colitis, or biliary tract or pancreatic disease.
●Perirectal tenderness may suggest anorectal infection from gonorrhea or Chlamydia or lymphogranuloma venereum.
●Overt blood or guaiac-positive stools in a patient with advanced immunosuppression may suggest mucosal disease such as CMV or Herpes simplex virus (HSV) proctitis, or neoplasia.
●A full physical examination, including ophthalmologic evaluation in the patient with advanced immunosuppression, is important since there may be other clues as to the etiology of diarrhea, such as concomitant retinitis and colitis from CMV infection.
LABORATORY TESTING — Laboratory tests beyond routine studies (eg, complete blood count, CD4 count, viral load, liver function, and renal function) depend upon the severity of illness and the information obtained from the history and physical examination (see 'History' above and 'Physical examination' above). As examples, in the setting of severe malnutrition, prealbumin and vitamin levels should be checked; if considering pancreatic malabsorption, fecal elastase can be measured. Additional testing for specific infections is discussed below. (See 'Diagnostic studies' below.)
DIAGNOSTIC STUDIES — The goal of an extensive evaluation is to identify any treatable cause of diarrheal disease. If pathogen-negative diarrhea occurs in a patient not on antiretroviral therapy (ART), the patient may improve after ART has been initiated. (See "Selecting antiretroviral regimens for treatment-naïve persons with HIV-1: General approach".)
Prior to the introduction of combination antiretroviral therapy, more than 50 percent of diarrheal illnesses in individuals with HIV had no readily identifiable pathogen, although this number was reduced somewhat if a comprehensive diagnostic workup was undertaken [10,22].
Stool examination — The initial evaluation of a patient with diarrhea should include stool examination and cultures. Stool examinations should be ordered for culture of bacteria, C. difficile toxin assay, and examination for ova and parasites (table 2). An acid-fast smear or immunofluorescent stain should also be requested to look for Cryptosporidium, Isospora, and Cyclospora. In patients with CD4 counts <100 cells/microL, the possibility of Microsporidium should also be investigated via trichrome staining of a stool specimen . If available, molecular testing (eg, multiplex polymerase chain reaction) may also be useful for detecting diarrheal pathogens. (See "Approach to the adult with acute diarrhea in resource-rich settings", section on 'Evaluation' and "Approach to the adult with acute diarrhea in resource-limited countries" and "Approach to the adult with chronic diarrhea in resource-abundant settings".)
A thorough evaluation with multiple specimens (including three samples for special stains and ova and parasites) will hopefully obviate the need for more invasive testing. However, biopsy is still required to confirm infection with certain organisms (eg, Mycobacterium avium complex [MAC], cytomegalovirus [CMV]). (See 'Endoscopy' below.)
Blood cultures — If disseminated MAC infection is a diagnostic consideration, blood should also be obtained in fungal isolator tubes for culture.
Endoscopy — In patients with advanced immunocompromise and either persistent diarrhea or diarrhea with fever, more extensive workup is reasonable, with small bowel biopsies looking for MAC, lymphoma, or microsporidiosis. In patients with colitis and negative stool examinations, colonoscopy and biopsy looking for CMV or other inflammatory enteridites should be considered. A history of guaiac positive stools in the setting of weight loss may be a presenting symptom of Kaposi's sarcoma, which can be seen as vascular mucosal lesions on endoscopy. Skin lesions are usually present with disseminated Kaposi's sarcoma.
In the patient with suspected colitis, if a diagnosis is not made with careful stool analysis, we recommend sigmoidoscopy with biopsy as the next procedure. Biopsies should be preferentially taken of any abnormal appearing mucosa. While colonoscopy, rather than sigmoidoscopy, has been advocated for enhanced diagnosis of CMV confined to the right colon [34,35], we reserve this procedure for patients in whom the sigmoidoscopy is negative as a more cost-effective approach.
This approach is supported by a prospective study of 79 patients with HIV-related diarrhea who underwent evaluation with stool studies, upper endoscopy, and colonoscopy . Of these patients, endoscopic evaluation provided a new diagnosis in 22 patients (28 percent). Biopsies of the sigmoid colon alone were sufficient to establish the diagnosis of CMV in all 15 patients. The majority of patients with a positive terminal ileal biopsy had microsporidiosis, which could have also been diagnosed by a modified trichrome stain of stool . Another study from Taiwan confirmed the value of endoscopy after two weeks of failed symptomatic therapy .
If lower tract evaluation is negative, upper endoscopy can occasionally uncover proximal small bowel infection by Cryptosporidium, Microsporidium, histoplasmosis or MAC [34,39].
The decision to perform upper or lower endoscopy first is suggested by the symptom complex. Classic features of colitis (cramps, fecal leukocytes, bloody stool and/or fever) suggest lower endoscopy will have the highest yield. Symptoms suggesting enteritis (watery high-volume diarrhea without fever or fecal leukocytes) would suggest proceeding with upper endoscopy as the initial test. (See 'Regional involvement' above.)
Imaging — Abdominal computed tomography (CT) using oral and intravenous contrast may be useful for patients with diarrhea and concomitant significant abdominal pain since imaging may show evidence of:
●Colitis (CMV, herpes simplex virus [HSV], C. difficile) or inflammatory bowel disease
●Abdominal adenopathy or hepatosplenomegaly (MAC, tuberculosis, histoplasmosis, lymphoma)
●Biliary tract disease
Other contrast studies (eg, barium studies) are generally not useful in evaluating diarrhea in these patients since most disorders require mucosal biopsy. In addition, barium may interfere with CT imaging and examination of stool samples. (See 'Stool examination' above.)
COMPLICATIONS — Malnutrition can be a serious complication of diarrheal disease in patients with HIV, since malabsorption of nutrients may accompany diarrhea and people with diarrhea may minimize intake because of intestinal symptoms or to control the frequency of stooling. Malnutrition remains a strong predictor of morbidity and mortality in those infected with HIV.
Significant electrolyte disturbances can also occur, particularly in the setting of severe cryptosporidiosis.
EMPIRIC THERAPY — If stool evaluation and flexible sigmoidoscopy are nondiagnostic, some clinicians prefer empiric antibiotic therapy with a quinolone and metronidazole for treatment of potential undiagnosed pathogen, culture-negative Campylobacter, or Giardia. However, small bowel overgrowth as a cause of diarrhea is very rare. In addition, antibiotics may lead to additional adverse events. We generally do not recommend this strategy unless the patient has a clinical history strongly suggestive of a possible diagnosis (ie, the sexual partner was recently diagnosed with Giardia). Empiric therapy directed towards amebic colitis is also not recommended in developed countries.
If a particular antiretroviral medication is the culprit (eg, ritonavir), alternative medications should be substituted, whenever possible. (See "Switching antiretroviral therapy for adults with HIV-1 and a suppressed viral load", section on 'Gastrointestinal intolerance'.)
If chronic diarrhea continues unabated without a diagnosis, symptomatic therapy with an antimotility drug (eg, loperamide or diphenoxylate with atropine [Lomotil]) can be initiated. An alternative to an antimotility agent is crofelemer, a botanical agent that blocks chloride secretion and accompanying high-volume water loss in diarrhea . Crofelemer was approved by the US Food and Drug Administration in 2012 for noninfectious diarrhea in patients with HIV receiving antiretroviral therapy . The safety and efficacy of crofelemer were evaluated in a trial of 374 patients with HIV and noninfectious diarrhea; 17.6 percent of patients receiving crofelemer experienced clinical response compared with 8 percent of patients receiving placebo. The dosage of crofelemer is 125 mg orally twice daily. (See "Approach to the adult with acute diarrhea in resource-rich settings", section on 'Symptomatic therapy'.)
Attention should also be given to nutritional evaluation, counseling, and support if the body mass index (BMI) is low or if otherwise unexplained weight loss is present. There are few data on the use of antimotility agents for chronic diarrhea in patients with AIDS .
Zinc deficiency, which is commonly found in patients with HIV, has been associated with pathogen negative diarrhea . However, a randomized controlled trial of dietary zinc supplementation had no significant effect on the duration or remission of diarrhea in adults with HIV .
Expectant observation and maintenance of hydration are probably appropriate in the patient with acute small bowel, watery diarrhea and a CD4 count that approaches normal, since these syndromes are likely to be self-limited and relatively benign. (See "Approach to the adult with acute diarrhea in resource-rich settings".)
SUMMARY AND RECOMMENDATIONS
●Diarrhea can cause significant morbidity in patients with HIV and may be due to a multitude of etiologies, including infection, malignancy, or medications. Diarrhea is also an independent predictor of reduced quality of life. (See 'Introduction' above.)
●Prior to the use of combination antiretroviral therapy in the United States, chronic diarrhea was responsible for a significant proportion of AIDS-defining conditions. However, the incidence of infectious causes of diarrhea in patients with HIV and low CD4 counts (<200 cells/microL) has declined. Chronic diarrhea remains an important source of morbidity in resource-limited settings where antiretroviral therapy may be less available. (See 'Incidence' above.)
●Diarrheal disease in individuals with HIV is frequently caused by infectious agents but may also be due to infiltrative diseases, such as lymphoma or Kaposi's sarcoma. (See 'Pathogenesis' above.)
●A detailed history should include the duration of symptoms, frequency and characteristics of stool, amount and pace of weight loss, and other abdominal or constitutional symptoms. Current medications should be reviewed. (See 'History' above.)
●In patients who are taking antiretroviral therapy, medication-induced diarrhea should be considered, particularly when diarrhea is the sole presenting symptom and there is a temporal association. (See 'History' above.)
●A careful physical examination is necessary to help determine the degree of wasting or any particular findings that may point to specific diseases. For example, fever and wasting may suggest an underlying opportunistic infection. (See 'Physical examination' above.)
●Helpful diagnostic studies include stool and blood cultures. Endoscopy and CT imaging may be required if the initial noninvasive workup is nondiagnostic. (See 'Diagnostic studies' above.)
●Complications of severe diarrhea include weight loss, malnutrition, and electrolyte disturbance. (See 'Complications' above.)
●If chronic diarrhea continues unabated without a diagnosis, symptomatic therapy with an antimotility drug can be initiated. (See 'Empiric therapy' above.)
ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Christine Wanke, MD, who contributed to an earlier version of this topic review.
We are saddened by the death of John G Bartlett, MD, who passed away in January 2021. UpToDate gratefully acknowledges Dr. Bartlett's role as section editor on this topic, his tenure as the founding Editor-in-Chief for UpToDate in Infectious Diseases, and his dedicated and longstanding involvement with the UpToDate program.
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